In cancer patients, determination of whether a malignancy has spread is the single most important factor used to develop a therapeutic plan and to predict prognosis. In most cases cancer cells initially spread through regional lymph nodes. Therefore, clinical evaluation for the presence of regional lymph node metastases is of paramount importance. Unfortunately, there are no real-time, non-invasive clinical methods that can reliably detect and diagnose micrometastases in lymph node. Therefore, there is an urgent clinical need for an imaging technique that is widely available, is non-invasive and simple to perform, is safe, and can reliably detect and adequately diagnose lymph node micrometastases in real time. The overall goal of our research program is to develop an advanced, in-vivo, noninvasive, molecular specific imaging technology, i.e., integrated ultrasound and photoacoustic imaging combined with targeted plasmonic nanosensors, capable of immediate and accurate assessment of sentinel lymph node micrometastases in real time. The underlying hypothesis of this project is that photoacoustic imaging integrated with widely used clinical ultrasound imaging is possible and both ultrasound and photoacoustic imaging can be performed in real time, yielding an immediate diagnosis and allowing early implementation of treatment. A wide range of scientific and engineering, biomedical and clinical problems must be addressed to fully explore the capabilities of molecular specific ultrasound and photoacoustic lymphatic (MS-USPAL) imaging in detection and characterization of sentinel lymph node micrometastases. The central theme of the current application is threefold: to design and build a laboratory prototype of the integrated ultrasound and photoacoustic imaging system, to develop lymphatic contrast agent based on gold bioconjugated plasmonic nanosensors, and to initially test the develop imaging technology in 3D tissue phantoms, small animal model and, finally, excised cancerous tissue samples. Therefore, all theoretical and experimental studies will be conducted to evaluate applicability of the developed MS-USPAL imaging system for sentinel lymph node micrometastases. At the end of the study, we will outline the design and technical specifications of a clinical MS-USPAL imaging system.